Ocular Pharmacodynamics of Intravitreal Faricimab in Patients With Neovascular Age-Related Macular Degeneration or Diabetic Macular Edema
Cheikh Diack, Robert L. Avery, Chui Ming Gemmy Cheung, Karl G. Csaky, Leonid Gibiansky, Félix Jaminion, Ekaterina Gibiansky, Denise Sickert, Ivo Stoilov, Valérie Cosson, Katrijn Bogman
Abstract
Purpose: Evaluate the ocular pharmacodynamics (PD) of intravitreal faricimab, a bispecific inhibitor of angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A), in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME). Methods: Aqueous humor (AH) samples (1025 free Ang-2 concentrations and 1345 free VEGF-A concentrations) were collected from approximately 300 faricimab-treated patients with nAMD or DME in phase 2/3 trials. A population pharmacokinetic pharmacodynamic (popPKPD) model was developed to describe the dynamic effect of faricimab on free AH Ang-2 and VEGF-A. Results: Mean baseline Ang-2 concentrations were 8.1 and 13.4 pg/mL in patients with nAMD and DME, respectively. The corresponding mean baseline VEGF-A concentrations were 58 and 135 pg/mL, respectively. Overall, approximately 79% of Ang-2 (84% within 8 weeks postdose and 55% beyond 12 weeks postdose) and 7% of VEGF-A postdose observations were below the lower limit of quantification. Model-derived Ang-2 and VEGF-A concentration-time profiles for patients on every 4-week/every 8-week dosing were predicted to maintain greater than 50% suppression of Ang-2 concentrations for the entire dosing period. Patients on every 12-week/16-week dosing were predicted to have greater than 50% Ang-2 suppression for 12 or more weeks, whereas 50% VEGF-A suppression was maintained for 9 to 10 weeks. At 8 weeks postdose, the median Ang-2 concentrations remained suppressed by approximately 80%. At 16 weeks postdose, the median VEGF-A concentrations returned to baseline, but median Ang-2 levels remained below baseline. Conclusions: A popPKPD analysis demonstrated faricimab's rapid and sustained suppression of AH Ang-2 and VEGF-A. Translational Relevance: A popPKPD analysis suggested that sustained suppression of ocular Ang-2 contributes to faricimab's extended durability, observed in clinical trials.